Cystic Fibrosis

Clinical Features
Cystic fibrosis is a heterogeneous recessive genetic
disorder with features that reflect mutations in the
cystic fibrosis transmembrane conductance
regulator (CFTR) gene.
Most common lethal inherited disease in white
persons, Typically presents in childhood
7% of CF patients diagnosed as adults
Classic cystic fibrosis is characterized by chronic
bacterial infection e.g Pseudomonas aeruginosa ( of
the airways and sinuses, fat maldigestion due to
pancreatic exocrine insufficiency, infertility in
males due to obstructive azoospermia, and elevated
concentrations of chloride in sweat.
Genetics of CF

Autosomal recessive
Gene located on chromosome 7
Prevalence- varies with ethnic origin
1 in 3000 live births in Caucasians in North America and
Northern Europe
1 in 17,000 live births of African Americans
1 in 90,000 live births in Hawaiian Asians
Genetics of CF

Most common mutation

Occurs in 70% of CF chromosomes
3 base pair deletion leading to absence of phenylalanine at
position 508 (F508) of the CF transmembrane conductance
regulator (CFTR)
Genetics of CF

The CFTR protein

Cyclic AMP regulated chloride channel
Regulator of other ion channels
Found in the plasma membrane of normal epithelial cells
Genetics of CF

F508 mutation leads to improper processing and

intracellular degradation of the CFTR protein

Other mutations in the CF gene produce fully processed

CFTR proteins that are either non-functional or partially
functional
Genetics of CF

Epithelial dysfunction
Epithelia containing CFTR protein exhibit array of normal
functions
Volume absorbing (airway, distal intestine)
Salt absorbing without volume (sweat ducts)
Volume secretory (proximal intestine, pancreas)
Dysfunction in CFTR gene leads to different effects on
patterns of electrolyte and water transport
 Pathophysiology
Defective gene

Mutations within this gene

increased chloride secretion and
sodium absorption mucus
accumulation and plugging of the
airways decreased mucus
clearing chronic infections
(e.gPseudomonas aeruginosa) and
bronchiectasis.
Pathophysiology

Gastrointestinal
Pancreas
Absence of CFTR limits function of chloride-bicarbonate
exchanger to secrete bicarbonate
Leads to retention of enzymes in the pancreas, destruction of
pancreatic tissue.
Intestine
Decrease in water secretion leads to thickened mucus and
dessicated intraluminal contents
Obstruction of small and large intestines
Pathophysiology
Gastrointestinal
Biliary tree
Retention of biliary secretion
Focal biliary cirrhosis
Bile duct proliferation
Chronic cholecystitis, cholelithiasis
Sweat
Normal volume of sweat
Inability to reabsorb NaCl from sweat as it passes through
sweat duct
 The main signs and symptoms
Salty-tastingskin
Poor growth, and poor weight gain despite normal food
intake
Accumulation of thick, sticky mucus
Frequent chest infections
Coughing or shortness of breath
 Management is based on the affected
symptoms and can be listed as:
Respiratory:
postural drainage,
bronchodilators,
IV/PO antibiotics (for infective
exacerbations and prophylaxis);
Gastrointestinal:
pancreatic enzyme replacement,
fat-soluble vitamin replacement therapy,
ursodeoxycholic acid treatment if
impaired liver function exists.
Gene therapy, which entails transferring the
CFTR gene to the lungs using liposomes and
adenovirus vectors. Although promising, gene
therapy still carries problems concerning
efficiency and target delivery of the CFTR
gene.
 A 9 month-old infant has a pattern of recurrent
hospitalizations of respiratory difficulty,
recurrent bronchitis with thick mucus
production and poor weight gain with thin
extremities. His history revealed a meconium
ileus at birth.
You are told that a patient in clinic has been diagnosed with
cystic fibrosis using the sodium chloride sweat test. Which of
the following results from the latter test would indicate a
positive diagnosis of cystic fibrosis?
A. Sodium chloride <40 mmol/L
B. Sodium chloride >60 mmol/L
C. Sodium chloride >50 mmol/L
D. Sodium chloride <60 mmol/L
E. Sodium chloride <30 mmol/L
 B Mutations within this gene lead to increased chloride secretion
and sodium absorption respectively, resulting in mucus
accumulation and plugging of the airways leading to chronic
infections and bronchiectasis.
Neonates present with failure to thrive, meconium ileus and
rectal prolapse. Presenting clinical features in children and young
adults can be categorized into: (1) Respiratory: cough, wheeze,
recurrent infections, bronchiectasis, pneumothorax, haemoptysis,
respiratory failure, corpulmonale; (2) Gastrointestinal: pancreatic
insufficiency leading to diabetes mellitus and/or steatorrhoea,
distal intestinal obstruction syndrome which is the equivalent of
meconium ileus in neonates, gallstones, cirrhosis. Other features
include male infertility, osteoporosis, arthritis, vasculitis,
hypertrophic pulmonary osteoathropathy (HPOA), nasal polyps
and sinusitis.
Diagnosis is usually made using the sodium chloride sweat test. A
positive test for cystic fibrosis usually indicates a reading of >60
mmol/L (B) (chloride levels being greater than sodium). Genetic
testing can also reveal common mutations in the CFTR gene.
Faecal elastase can be measured to assess exocrine pancreatic
dysfunction.
Which of the following organisms, responsible for causing
chronic pneumonia, ismost commonly found in patients with
longstanding cystic fibrosis?
A. L. pneumophilia
B. S. pneumonia
C. Burkholderia cepacia
D. Pseudomonas aeruginosa
E. H. influenza
 D Mucus build-up coupled with decreased
mucociliary clearance results in clogging
of the airways and an inflammation-rich
environment which predisposes patients
with cystic fibrosis to chronic lower
respiratory tract infections (LRTIs). The
three most common organisms
responsible for causing LRTIs in cystic
fibrosis are S.aureus, H. influenza and P.
aeruginosa (D). In the early stages of the
condition, S. aureus and H.influenza
colonize and infect the lung parenchyma.
With time and chronicity of disease, P.
aeruginosa and Burkholderia cepacia (C)
predominate with 80 per cent of patients
harbouring the former and 3.5 per cent
the latter, respectively.